tbuckley/cabot-search huggingface dataset:
Abstract 1303: FAP-targeted molecular radiotherapy attenuates tumor growth and synergizes with immunotherapy for the treatment of malignant melanoma
Authors: Kathleen M. Capaccione, Mikhail Doubrovin, Brian Braumuller, Dvora Leibowiz, Nikunj Bhatt, Andrei Molotkov, Michael Kissner, Fatemeh Momen-Heravi, Akiva Mintz
Journal: Cancer Research (2022)

Abstract Immunotherapy has drastically improved outcomes in many patients with melanoma, however the majority do not attain a durable response to treatment and therefore additional agents are desperately needed. Here, we tested the efficacy of 177Lu-FAPI-04, a novel FAP-targeted radiotherapy, alone and in combination with anti-PD-1 and anti-CTLA-4 immunotherapy in a mouse model of melanoma to attenuate tumor growth. Using B16F10 murine melanoma cells, we implanted tumors in C57BL/6 mice. Animals were divided into four groups: untreated control, molecular targeted 177Lu-FAPI-04 radiotherapy treatment, immunotherapy treatment, and combined radio- and immunotherapy treatment. We assessed tumor growth over time and animals were sacrificed at 21 days. After sacrifice, tumors were dissected out and preserved for immunohistochemistry and flow cytometry. Growth curves demonstrated that immunotherapy and radiotherapy each individually attenuated tumor growth, but together they resulted in tumor regression in the majority of animals. Immunohistochemistry demonstrated increased caspase-3 staining in tumors treated with combined 177Lu-FAPI-04 radiotherapy and immunotherapy compared to untreated tumors or tumors treated with either therapy alone indicating an increase in apoptotic cell death. Ki67 expression exhibited inverse staining with moderate expression in untreated samples, low expression in immunotherapy and radiotherapy treated samples, and no staining in tumors treated with combined therapy. Flow cytometric analysis demonstrated that tumors treated with either therapy exhibited an increase in M2 macrophages, however this population was obliterated in dual-treated tumors. Together, these data support that targeting FAP with targeted radiotherapy is an effective treatment which synergizes with immunotherapy to modulate cells of the myeloid lineage as an effective anticancer therapy for melanoma. Future translational studies are needed to further study the synergies between FAP-targeted radiotherapies and immunotherapy. Citation Format: Kathleen M. Capaccione, Mikhail Doubrovin, Brian Braumuller, Dvora Leibowiz, Nikunj Bhatt, Andrei Molotkov, Michael Kissner, Fatemeh Momen-Heravi, Akiva Mintz. FAP-targeted molecular radiotherapy attenuates tumor growth and synergizes with immunotherapy for the treatment of malignant melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1303.
Abstract 2768: Whole-slide multispectral imaging reveals the immune subtypes of melanoma associated with the tumor microenvironment
Authors: Bhavika Patel, Stephanie Allen, Brittney Boldt, Najiba Mammadova, Agnes Haggerty, Navi Mehra
Journal: Cancer Research (2022)

Abstract Immunotherapy and precision medicine are rapidly developing approaches to cancer therapy. Biomarkers that detect the tumor and tumor microenvironment allow for the development of strategies that accelerate the advancement of treatments to enhance a patient’s immune system. Akoya’s MOTiF™ PD-1/PD-L1 Auto Melanoma Kit is a validated, multiplex immunoassay enabling detection of the 6 most clinically relevant immuno-oncology and spatial biomarkers: FoxP3, PD-L1, Sox10/S100, PD-1, CD8 and CD68. In this study, the MOTiF™ PD-1/PD-L1 panel was used to analyze the tumor microenvironment and specifically assess immune phenotypes within melanoma samples from 3 patients. This study demonstrates a fully optimized and end-to-end workflow solution for biomarker discovery in melanoma. We demonstrate the utility of Akoya’s MOTiF™ PD-1/PD-L1 Melanoma panel kit in studying the cellular diversity while retaining spatial context. Stained slides were analyzed using the InForm® and PhenoptrReports image analysis platforms to identify phenotypes and better understand spatial relationships between cell phenotypes. The MOTiF™ PD-1/PD-L1 panel kit provides reproducibility across different patient samples. This data provides insight into the innate and adaptive immune landscape for targeted design of new immunotherapies as well as improved efficacy and reduced toxicity in the treatment of melanoma. Citation Format: Bhavika Patel, Stephanie Allen, Brittney Boldt, Najiba Mammadova, Agnes Haggerty, Navi Mehra. Whole-slide multispectral imaging reveals the immune subtypes of melanoma associated with the tumor microenvironment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2768.
Abstract 5950: A novel biguanide as a potential head and neck cancer therapeutic in Fanconi anemia
Authors: Hunter Archibald, Beverly Wuertz, Frank Ondrey
Journal: Cancer Research (2022)

Abstract Introduction: Fanconi Anemia (FA) patients develop head and neck squamous cell carcinoma (HNSCC) at significantly elevated rates and conventional adjunctive chemotherapy and radiation are exquisitely toxic to these patients. We endeavor to find a safer chemotherapeutic agent for treatment of head and neck cancer in this population. Currently, agents such as metformin are in FA clinical trials for marrow failure and are also high interest agents in head and neck cancer chemoprevention. HNSCC in FA is a disease model that has applications to typical head and neck cancer, as its mutational defects are felt to be similar. Methods: We completed cell proliferation assays on FA-derived HNSCC cell lines MOP FA-1 and VU-1131. MTT, Cell Titer Glo, trypan blue, and clonogenic assays were completed on each cell line to evaluate the effect of N1-hexyl-N5-benzyl-biguanide (HBB) in comparison with standard cisplatin chemotherapy. We also compared the caspase activity in an effort to evaluate a putative mechanism of HBB cellular inhibition. Results: HBB showed a statistically significant dose-dependent inhibition of cellular proliferation. In MTT assays, 5 uM HBB showed 28-46% inhibition at 72 hours and 10uM HBB showed 77-82% inhibition at 72 hours. There was an additive inhibition of cellular proliferation when HBB was combined with low-dose cisplatin. Conclusion: HBB is a novel biguanide that inhibited cellular proliferation in two FA HNSCC cell lines and chemosensitized to low-dose cisplatin. This may be an alternative adjunct treatment agent, or may be chemosensitizing for low-dose cytotoxic agents such as platinum-based chemotherapeutics in this unique population. Citation Format: Hunter Archibald, Beverly Wuertz, Frank Ondrey. A novel biguanide as a potential head and neck cancer therapeutic in Fanconi anemia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5950.
Ancestral Sequence Reconstruction of a Cytochrome P450 Family Involved in Chemical Defense Reveals the Functional Evolution of a Promiscuous, Xenobiotic-Metabolizing Enzyme in Vertebrates
Authors: Kurt L. Harris, Raine E.S. Thomson, Yosephine Gumulya, Gabriel Foley, Saskya E. Carrera-Pacheco, Parnayan Syed, Tomasz Janosik, Ann-Sofie Sandinge, Shalini Andersson, Ulrik Jurva, Mikael Bodén, Elizabeth M.J. Gillam
Journal: Molecular Biology and Evolution (2022)

Abstract The cytochrome P450 family 1 enzymes (CYP1s) are a diverse family of hemoprotein monooxygenases, which metabolize many xenobiotics including numerous environmental carcinogens. However, their historical function and evolution remain largely unstudied. Here we investigate CYP1 evolution via the reconstruction and characterization of the vertebrate CYP1 ancestors. Younger ancestors and extant forms generally demonstrated higher activity toward typical CYP1 xenobiotic and steroid substrates than older ancestors, suggesting significant diversification away from the original CYP1 function. Caffeine metabolism appears to be a recently evolved trait of the CYP1A subfamily, observed in the mammalian CYP1A lineage, and may parallel the recent evolution of caffeine synthesis in multiple separate plant species. Likewise, the aryl hydrocarbon receptor agonist, 6-formylindolo[3,2-b]carbazole (FICZ) was metabolized to a greater extent by certain younger ancestors and extant forms, suggesting that activity toward FICZ increased in specific CYP1 evolutionary branches, a process that may have occurred in parallel to the exploitation of land where UV-exposure was higher than in aquatic environments. As observed with previous reconstructions of P450 enzymes, thermostability correlated with evolutionary age; the oldest ancestor was up to 35 °C more thermostable than the extant forms, with a 10T50 (temperature at which 50% of the hemoprotein remains intact after 10 min) of 71 °C. This robustness may have facilitated evolutionary diversification of the CYP1s by buffering the destabilizing effects of mutations that conferred novel functions, a phenomenon which may also be useful in exploiting the catalytic versatility of these ancestral enzymes for commercial application as biocatalysts.
Abstract LB073: Improving early career faculty research programs: Underrepresented Biomedical Researcher Scholars Program
Authors: Debra Murray, Susan Fernbach
Journal: Cancer Research (2022)

Abstract According to the U.S. Department of Education in Fall 2018, full-time faculty in degree-granting postsecondary institutions were ~40% White males; 35% White females; 7% Asian/Pacific Islander males; 5% Asian/Pacific Islander females; and 3% each Black males, Black females, Hispanic males, and Hispanic females.1 Under-representation is one of the barriers to success for African American and Hispanic faculty. Barriers to women’s career advancement from underrepresented groups in academic medicine, science, and engineering and obtaining external research funding support for African American faculty do not occur in a vacuum and co-exist with barriers to research productivity overall.2 This data establishes the necessity of increasing representation, creating more accessible research opportunities, building networks, mentoring relationships in STEM-related fields, obtaining a diverse scientific workforce, and ensuring the success of all underrepresented in biomedical research (UBR) trainees and early career faculty. The All of Us Evenings with Genetics (AoUEwG) Research Program provides training to support Early Career Faculty and Senior Postdoctoral fellowship in cancer research. This engagement program includes Evenings With Genetics seminars, where regional and national campus audiences will be introduced to research opportunities available through the All of Us research hub; the Underrepresented Biomedical Researcher Faculty Summit UBRFS), where summit attendees will take part in using the All of Us research hub and receive data science training and professional development; and the UBRFS Scholars Program, where conference participants will receive yearlong support after the summit, including monthly multidisciplinary research team meetings, quarterly meetings, and mentor support. The AoUEwG Research Program aims to increase research productivity among UBR early career faculty and support their promotion to the next career level. Citation Format: Debra Murray, Susan Fernbach. Improving early career faculty research programs: Underrepresented Biomedical Researcher Scholars Program [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB073.
Abstract 5441: Discovery of a novel RAD51 inhibitor SCR-6992 targeting homologous recombination pathways in cancer
Authors: Peng Gu, Liting Xue, Ping Chen, Wenjing Li, Ya Geng, Feng Zhou, Guimei Yang, Xiaohong Hou, Chunyan Zhao, Wenqing Yang, Renhong Tang
Journal: Cancer Research (2022)

Abstract Targeting DNA damage response (DDR) pathways has been proposed as an approach for amplifying tumor-specific replicative lesions. RAD51 plays a central role in the DDR pathway, and thus represents a promising anti-tumor target. We here report the discovery of a series of next generation RAD51 inhibitors that can prevent RAD51 foci formation and particularly, a pre-clinical candidate molecule SCR-6992 with potent anti-tumor efficacies and desirable pre-clinical development drug properties. SCR-6992 exhibits remarkable anti-proliferative potency in human lymphoma Daudi cells in vitro (IC50 = 12 nM) while has no inhibitory effect in normal human cells. The combination of SCR-6992 with chemotherapeutic agents or DDR-targeting drugs produces synergistical anti-cancer response in lymphoma and solid tumor cell lines. Furthermore, SCR-6992 significantly inhibits tumor growth in Daudi xenograft tumor model with the tumor regression observed when dosed orally at 80 mg/kg/day. SCR-6992 also shows acceptable translational drug properties and pharmacokinetic profiles in both rodents and dogs. SCR-6992 was well tolerated in rats and dogs in 14-day dose range finding studies without noted hematological or gastrointestinal toxicities, when dosed up to 200 mg/kg and 40 mg/kg, respectively. Taken together, SCR-6992 demonstrates as an effective RAD51 inhibitor with encouraging anti-tumor activities and favorable development drug properties. The clinical development plans of SCR-6992 have been formulated for hematologic malignancies and solid tumors. Citation Format: Peng Gu, Liting Xue, Ping Chen, Wenjing Li, Ya Geng, Feng Zhou, Guimei Yang, Xiaohong Hou, Chunyan Zhao, Wenqing Yang, Renhong Tang. Discovery of a novel RAD51 inhibitor SCR-6992 targeting homologous recombination pathways in cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5441.
Abstract 5347: miR-15a &amp; miR-20b enhance sorafenib sensitivity of hepatocellular carcinoma through repressing CDC37L1 and consequent PPIA downregulation
Authors: Li Li, Shijun Yu, Jingde Chen, Ming Quan, Yong Gao, Yandong Li
Journal: Cancer Research (2022)

Abstract Sorafenib is a classical targeted drug for the treatment of advanced hepatocellular carcinoma (HCC), but intrinsic resistance severely limits its therapeutic effects. In the present study, we aimed to identify crucial genes in HCC cells that affect sorafenib resistance by a CRISPR/Cas9 genome-scale screening. Among the candidates, two miRNAs, miR-15a and miR-20b, were finally identified as the essential sorafenib-sensitizing genes of HCC cells. In parallel, Cell Counting Kit-8 (CCK-8) assay,colony formation assays and flow cytometric analysis were carried out to assess cell proliferation and survival, whereas tumor growth in vivo was assessed using xenograft models. The results indicated that the deficiency of miR-15a and miR-20b contributed to sorafenib resistance of HCC cells. By combination of various bioinformatics tools, Cell division cycle 37 like 1 (CDC37L1) was identified as a common target gene of miR-15a and miR-20b. Further cellular and molecular biology experiments demonstrated CDC37L1 was negatively regulated by the two miRNAs, and CDC37L1 could enhance sorafenib resistance of HCC in vitro and in vivo. Mechanistically, we carried out SDS-PAGE and silver staining assays followed by mass spectrometry to analyze the immunoprecipitated proteins of CDC37L1. Our findings indicated that CDC37L1, as a cochaperone, effectively increased the expression of PPIA through strengthen the binding between HSP90 and PPIA. Additionally, CDC37L1 and PPIA expression were examined in a tissue microarray containing 80 pairs of HCC and normal tissues derived from patients who received sorafenib treatment via immunohistochemistry (IHC) staining, the results revealed a positive association between CDC37L1 and PPIA expression, and high expression of CDC37L1 and PPIA predicted worse prognosis of HCC patients after sorafenib therapy. Taken together, our findings suggest that both miR-15a and miR-20b play sorafenib-sensitizing roles in HCC by facilitating the complex of CDC37L1/HSP90/PPIA. Citation Format: Li Li, Shijun Yu, Jingde Chen, Ming Quan, Yong Gao, Yandong Li. miR-15a &amp; miR-20b enhance sorafenib sensitivity of hepatocellular carcinoma through repressing CDC37L1 and consequent PPIA downregulation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5347.
Abstract 4247: Development of NK humanized mice models for the <i>in vivo</i> evaluation of NK cell engagers
Authors: Pauline Rettman, Dorothée Bourges, Laure-Marie Meyer, Ravi Rangara, Anna Ponchet-Lac, Nicolas Moindrot, Sukhvinder Sidhu, Céline Nicolazzi
Journal: Cancer Research (2022)

Abstract Novel immunotherapeutic strategies targeting Natural Killer (NK) cells using monoclonal or multi-specific antibodies and immune modulator molecules are under development and there is a pressing need to have suitable mouse models for the evaluation of these therapeutics. To date, there are no validated in vivo mouse models that support the development of fully functional human NK cells. In recent years, the adoptive transfer of human peripheral mononuclear blood cells or CD34+ stem cells into highly immunodeficient mouse strains mostly allowed the evaluation of T cell-based therapies. However, these humanized mouse models have limitations and do not show an optimal development of innate immune cells such as NK, dendritic or myeloid cells. This is mostly due to the poor interspecies cross-reactivity of key factors necessary for cell development and maturation, like cytokines and growth factors.Here, we report the development and characterization of robust in vivo models that allow the engraftment and maintenance of fully functional human NK (huNK) cells, using several strains of immunodeficient transgenic mice for human cytokines (IL-15). The optimal parameters (source of immune cells, pre-conditioning regimen, route of administration) were identified. These models were characterized and validated by flow cytometry, and in vivo efficacy studies using an anti-CD20 Ab.In summary, we developed several murine models that exhibit significant numbers of functional huNK cells maintained over time in vivo. Different sources of human immune cell (CD34+ HSC, huNK cells) were used to implant immunodeficient huIL15 transgenic mice. HuNK cells were monitored by flow cytometry in all tested models. We showed huNK engraftment in both irradiated and non-irradiated models and confirmed the maintenance of expression of important functional NK markers on these cells. Efficacy studies performed in disseminated models showed promising results as efficacy of an anti-CD20 Ab, rituximab, was improved in presence of huNK cells, thus confirming the engagement of huNK cells in vivo in these models. Overall, we have developed several models that can sustain fully functional huNK cells over a period of several weeks that can be proficiently recruited in vivo by various NK-based therapeutics. Citation Format: Pauline Rettman, Dorothée Bourges, Laure-Marie Meyer, Ravi Rangara, Anna Ponchet-Lac, Nicolas Moindrot, Sukhvinder Sidhu, Céline Nicolazzi. Development of NK humanized mice models for the in vivo evaluation of NK cell engagers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 4247.
Abstract 2435: EZH2 engages TGFb signaling to promote breast cancer bone metastasis via Integrin b1-FAK activation
Authors: Lin Zhang, Jingkun Qu, Yutao Qi, Yimin Duan, Yu-Wen Huang, Zhifen Zhou, Ping Li, Jun Yao, Beibei Huang, Shuxing Zhang, Dihua Yu
Journal: Cancer Research (2022)

Abstract Bone metastasis is a frequent complication of breast cancer, occurring in about 50-70% of breast cancer patients with late-stage disease. The lack of effective therapy suggests that the precise molecular mechanisms underlying bone metastasis are still unclear. Enhancer of zeste homolog 2 (EZH2) is considered a breast cancer oncogene and its expression is correlated with metastasis of breast cancer, but its function in bone metastasis has not been well explored. Herein we report that EZH2 promotes osteolytic metastasis of breast cancer through regulating transforming growth factor beta (TGFβ) signaling, a key pathway in bone metastasis. Knocking down EZH2 decreases bone metastasis incidence and outgrowth in vivo. EZH2 induces cancer cell proliferation and osteoclast maturation, when breast cancer cells are co-cultured with osteoblasts and osteoclasts together in vitro. Mechanistically, EZH2 increases transcription of ITGB1, which encodes for integrin β1. Integrin β1 activates focal adhesion kinase (FAK), which phosphorylates TGFβ receptor type I (TGFβRI) at tyrosine 182, thus enhances the binding of TGFβRI to TGFβ receptor type II (TGFβRII), therefore activates Smad2 and increases parathyroid hormone-like hormone (PTHLH) expression. Clinically applicable FAK inhibitors but not EZH2 methyltransferase inhibitor effectively inhibits breast cancer bone metastasis in vivo. Overall, our data signify integrin β1-FAK as a new downstream effector of EZH2 in breast cancer cells, and EZH2-integrin β1-FAK axis cooperates with TGFβ signaling pathway to promote bone metastasis of breast cancer. Citation Format: Lin Zhang, Jingkun Qu, Yutao Qi, Yimin Duan, Yu-Wen Huang, Zhifen Zhou, Ping Li, Jun Yao, Beibei Huang, Shuxing Zhang, Dihua Yu. EZH2 engages TGFb signaling to promote breast cancer bone metastasis via Integrin b1-FAK activation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2435.
Diagnostic parameters of cellular tests for Lyme borreliosis in Europe (VICTORY study): a case-control study
Authors: M E Baarsma, Freek R van de Schoor, Stefanie A Gauw, Hedwig D Vrijmoeth, Jeanine Ursinus, Nienke Goudriaan, Calin D Popa, Hadewych Jm Ter Hofstede, Mariska Mg Leeflang, Kristin Kremer, Cees C van den Wijngaard, Bart-Jan Kullberg, Leo Ab Joosten, Joppe W Hovius
Journal: The Lancet Infectious Diseases (2022)